Genetic Variation in Targets of Antidiabetic Drugs and Alzheimer Disease Risk

孟德尔随机化 医学 2型糖尿病 全基因组关联研究 糖尿病 胰岛素抵抗 遗传变异 内科学 磺酰脲 优势比 遗传关联 病例对照研究 胰岛素 2型糖尿病 生物信息学 内分泌学 生物 遗传学 单核苷酸多态性 基因型 遗传变异 人口 环境卫生 基因
作者
Bowen Tang,Yunzhang Wang,Xia Jiang,Madhav Thambisetty,Luigi Ferrucci,Kristina Johnell,Sara Hägg
出处
期刊:Neurology [Lippincott Williams & Wilkins]
卷期号:99 (7) 被引量:31
标识
DOI:10.1212/wnl.0000000000200771
摘要

Previous studies have highlighted antidiabetic drugs as repurposing candidates for Alzheimer disease (AD), but the disease-modifying effects are still unclear.A 2-sample mendelian randomization study design was applied to examine the association between genetic variation in the targets of 4 antidiabetic drug classes and AD risk. Genetic summary statistics for blood glucose were analyzed using UK Biobank data of 326,885 participants, whereas summary statistics for AD were retrieved from previous genome-wide association studies comprising 24,087 clinically diagnosed AD cases and 55,058 controls. Positive control analysis on type 2 diabetes mellitus (T2DM), insulin secretion, insulin resistance, and obesity-related traits was conducted to validate the selection of instrumental variables.In the positive control analysis, genetic variation in sulfonylurea targets was associated with higher insulin secretion, a lower risk of T2DM, and an increment in body mass index, waist circumference, and hip circumference, consistent with drug mechanistic actions and previous trial evidence. In the primary analysis, genetic variation in sulfonylurea targets was associated with a lower risk of AD (odds ratio [OR] = 0.38 per 1 mmol/L decrement in blood glucose, 95% CI 0.19-0.72, p = 0.0034). These results for sulfonylureas were largely unchanged in the sensitivity analysis using a genetic variant, rs757110, that has been validated to modulate the target proteins of sulfonylureas (OR = 0.35 per 1 mmol/L decrement in blood glucose, 95% CI 0.15-0.82, p = 0.016). An association between genetic variations in the glucagon-like peptide 1 (GLP-1) analogue target and a lower risk of AD was also observed (OR = 0.32 per 1 mmol/L decrement in blood glucose, 95% CI 0.13-0.79, p = 0.014). However, this result should be interpreted with caution because the positive control analyses for GLP-1 analogues did not comply with a weight-loss effect as shown in previous clinical trials. Results regarding other drug classes were inconclusive.Genetic variation in sulfonylurea targets was associated with a lower risk of AD, and future studies are warranted to clarify the underlying mechanistic pathways between sulfonylureas and AD.
最长约 10秒,即可获得该文献文件

科研通智能强力驱动
Strongly Powered by AbleSci AI
更新
PDF的下载单位、IP信息已删除 (2025-6-4)

科研通是完全免费的文献互助平台,具备全网最快的应助速度,最高的求助完成率。 对每一个文献求助,科研通都将尽心尽力,给求助人一个满意的交代。
实时播报
英姑应助九思采纳,获得10
1秒前
2秒前
2秒前
2秒前
3秒前
量子星尘发布了新的文献求助10
4秒前
JamesPei应助机灵的囧采纳,获得10
5秒前
llll发布了新的文献求助10
5秒前
orixero应助xmh采纳,获得10
5秒前
wq1020发布了新的文献求助10
7秒前
8秒前
皮皮蛙完成签到,获得积分10
8秒前
情怀应助常芹采纳,获得10
9秒前
肖肖发布了新的文献求助10
9秒前
9秒前
9秒前
10秒前
缥缈问柳完成签到,获得积分10
10秒前
10秒前
明理念桃完成签到,获得积分10
11秒前
13333发布了新的文献求助10
12秒前
Ava应助不吃意面的老番茄采纳,获得10
14秒前
14秒前
zhao完成签到 ,获得积分10
16秒前
17秒前
17秒前
17秒前
xmh完成签到,获得积分10
18秒前
什么也难不倒我完成签到 ,获得积分10
18秒前
19秒前
孟一发布了新的文献求助30
19秒前
20秒前
小幻完成签到,获得积分10
20秒前
好宝宝发布了新的文献求助10
21秒前
21秒前
乐天完成签到,获得积分10
22秒前
wuniuniu发布了新的文献求助10
22秒前
Happyness应助13333采纳,获得30
23秒前
23秒前
刻苦的书竹完成签到,获得积分20
23秒前
高分求助中
A new approach to the extrapolation of accelerated life test data 1000
ACSM’s Guidelines for Exercise Testing and Prescription, 12th edition 500
‘Unruly’ Children: Historical Fieldnotes and Learning Morality in a Taiwan Village (New Departures in Anthropology) 400
Indomethacinのヒトにおける経皮吸収 400
Phylogenetic study of the order Polydesmida (Myriapoda: Diplopoda) 370
基于可调谐半导体激光吸收光谱技术泄漏气体检测系统的研究 350
Robot-supported joining of reinforcement textiles with one-sided sewing heads 320
热门求助领域 (近24小时)
化学 材料科学 医学 生物 工程类 有机化学 生物化学 物理 内科学 纳米技术 计算机科学 化学工程 复合材料 遗传学 基因 物理化学 催化作用 冶金 细胞生物学 免疫学
热门帖子
关注 科研通微信公众号,转发送积分 3988838
求助须知:如何正确求助?哪些是违规求助? 3531250
关于积分的说明 11252914
捐赠科研通 3269838
什么是DOI,文献DOI怎么找? 1804820
邀请新用户注册赠送积分活动 881943
科研通“疑难数据库(出版商)”最低求助积分说明 809028